The majority of human cancers arise in the epithelial tissues of organs such as skin and colon. Uncontrolled proliferation of epithelial cells is often caused by aberrant signaling of growth factors and cytokines. A commonality among many epithelial tumors is an elevation of EGFR signaling. In fact, anti-EGFR strategies (EGFR monoclonal antibodies and small molecule tyrosine-kinase inhibitors; TKIs) are currently among the most common anti-cancer therapies. However, most anti-EGFR agents cause adverse side effects and are only partially effective due to quickly developed drug tolerance. We seek an alternative and novel strategy to treat EGFR-dependent carcinomas. Our proposal seeks to build on our recently made, and unexpected, discovery that TRPV3, a Ca2+ channel expressed in many epithelial tissues, including skin, colon, and prostate, is a key regulator of EGFR signaling. TRPV3 forms a signaling complex with TGF-a/EGFR; activation of EGFR leads to increased TRPV3 channel activity, which in turn stimulates TGF-a release mediated by ADAM-family sheddase. At the animal level, TRPV3-deficient mice exhibit similar hair/skin phenotypes as mice with defective TGF-a/EGFR signaling. Thus, TRPV3 could be a novel therapeutic target for skin and other epithelial cancers. Although ion channels are not known targets for cancer treatment, TRPV3 is recently reported to be a high-risk gene in colorectal cancer. Moreover, small molecule TRPV3 inhibitors are in clinical trials for reducing pain induced by inflammatory mediators, many of which are also potent tumor-promoting agents. Therefore, we specifically hypothesize that TRPV3 channel up-regulation in keratinocytes is a maladaption that accelerates skin tumorigenesis. Using animal models of skin carcinogenesis, we will investigate whether TRPV3 expression and channel function are up-regulated during epithelial malignancy, and whether genetic and pharmacological inactivation of TRPV3 may delay promotion/progression of epithelial tumors. Our first aim is to investigate TRPV3 expression/function during keratinocyte transformation and skin tumorigenesis. Our second aim is to study the roles of TRPV3 in the development of skin tumors using mice with genetically modified expression of TRPV3. Our third aim is to investigate the roles of TRPV3 in the development of skin tumors using TRPV3-specific small molecule inhibitors. Overall, the close interaction of TRPV3 and EGFR signaling on normal epidermis and the well-demonstrated role of EGFR signaling in cancer suggest a role of TRPV3 in epithelial tumorigenesis. The goal of this proposed research is to lay the groundwork necessary to develop new therapeutic strategies for skin and other epithelial cancers.